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Mitochondrial toxicity in hearts of CD-1 mice following perinatal exposure to AZT, 3TC, or AZT/3TC in combination.

Publication ,  Journal Article
Chan, SSL; Santos, JH; Meyer, JN; Mandavilli, BS; Cook, DL; McCash, CL; Kissling, GE; Nyska, A; Foley, JF; van Houten, B; Copeland, WC ...
Published in: Environmental and molecular mutagenesis
April 2007

Antiretroviral therapies based on nucleoside reverse transcriptase inhibitors (NRTIs), like zidovudine (3'-azido-3'-deoxythymidine; AZT) and lamivudine ((-)2',3'-dideoxy-3'-thiacytidine; 3TC), markedly reduce mother-to-child transmission of the human immunodeficiency virus (HIV). However, AZT induces damage in nuclear DNA of mice exposed in utero and postnatally, and mitochondrial DNA (mtDNA) damage has been observed in both human and mouse neonates following perinatal exposure to AZT and AZT/3TC in combination. To provide animal data modeling the NRTI-induced heart damage reported in human infants, we treated pregnant CD-1 mice throughout gestation and treated their pups by direct gavage from postnatal day (PND) 4 through PND 28 with daily doses of 150 mg/kg body weight (bw)/day AZT, 75 mg/kg bw/day 3TC, 125/62.5 mg/kg bw/day AZT/3TC, or the vehicle control. Half the pups were euthanized on PND 28; the remainder received no further dosing, and were euthanized at week 10. Heart tissue was collected, total DNA was extracted, and mtDNA copy number relative to nuclear DNA copy number, mtDNA damage, and mtDNA mutation assays were performed using PCR-based methods. Analyses revealed increases in mtDNA lesions in 4-week-old males and females treated with AZT or 3TC, but not in 10-week-old mice, suggesting that the damage resolved after treatment ceased. Interestingly, 10-week-old females treated with AZT/3TC had significant increases in mtDNA damage. Point mutations were elevated in 10-week-old females treated with AZT or AZT/3TC, but not 3TC; no increases in mutations were seen in either gender at 4 weeks of age. Our data suggest that AZT/3TC combination treatment produces greater mtDNA damage than either agent individually, and that female mice are more sensitive than males to AZT/3TC-induced mtDNA damage.

Duke Scholars

Published In

Environmental and molecular mutagenesis

DOI

EISSN

1098-2280

ISSN

0893-6692

Publication Date

April 2007

Volume

48

Issue

3-4

Start / End Page

190 / 200

Related Subject Headings

  • Zidovudine
  • Toxicology
  • Reverse Transcriptase Inhibitors
  • Prostaglandin-Endoperoxide Synthases
  • Pregnancy
  • Myocardium
  • Mutation
  • Mitochondria, Heart
  • Mice, Inbred Strains
  • Mice
 

Citation

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MLA
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Chan, S. S. L., Santos, J. H., Meyer, J. N., Mandavilli, B. S., Cook, D. L., McCash, C. L., … Bishop, J. B. (2007). Mitochondrial toxicity in hearts of CD-1 mice following perinatal exposure to AZT, 3TC, or AZT/3TC in combination. Environmental and Molecular Mutagenesis, 48(3–4), 190–200. https://doi.org/10.1002/em.20191
Chan, Sherine S. L., Janine H. Santos, Joel N. Meyer, Bhaskar S. Mandavilli, Dennis L. Cook, Consuelo L. McCash, Grace E. Kissling, et al. “Mitochondrial toxicity in hearts of CD-1 mice following perinatal exposure to AZT, 3TC, or AZT/3TC in combination.Environmental and Molecular Mutagenesis 48, no. 3–4 (April 2007): 190–200. https://doi.org/10.1002/em.20191.
Chan SSL, Santos JH, Meyer JN, Mandavilli BS, Cook DL, McCash CL, et al. Mitochondrial toxicity in hearts of CD-1 mice following perinatal exposure to AZT, 3TC, or AZT/3TC in combination. Environmental and molecular mutagenesis. 2007 Apr;48(3–4):190–200.
Chan, Sherine S. L., et al. “Mitochondrial toxicity in hearts of CD-1 mice following perinatal exposure to AZT, 3TC, or AZT/3TC in combination.Environmental and Molecular Mutagenesis, vol. 48, no. 3–4, Apr. 2007, pp. 190–200. Epmc, doi:10.1002/em.20191.
Chan SSL, Santos JH, Meyer JN, Mandavilli BS, Cook DL, McCash CL, Kissling GE, Nyska A, Foley JF, van Houten B, Copeland WC, Walker VE, Witt KL, Bishop JB. Mitochondrial toxicity in hearts of CD-1 mice following perinatal exposure to AZT, 3TC, or AZT/3TC in combination. Environmental and molecular mutagenesis. 2007 Apr;48(3–4):190–200.
Journal cover image

Published In

Environmental and molecular mutagenesis

DOI

EISSN

1098-2280

ISSN

0893-6692

Publication Date

April 2007

Volume

48

Issue

3-4

Start / End Page

190 / 200

Related Subject Headings

  • Zidovudine
  • Toxicology
  • Reverse Transcriptase Inhibitors
  • Prostaglandin-Endoperoxide Synthases
  • Pregnancy
  • Myocardium
  • Mutation
  • Mitochondria, Heart
  • Mice, Inbred Strains
  • Mice